Although the field of viral therapeutics has advanced in response to the need for treatments and prophylactics effective against diverse classes of viruses, the threat of viruses remain among several human populations across the world.
Retroviruses, such as HIV, continue to pose a threat to humans. There are many ways in which an agent can exhibit anti-retroviral activity (e.g., see DeClercq, Adv. Virus Res., 42: 1-55 (1993); DeClercq, J. Acquir. Immun. Def. Synd., 4: 207-218 (1991); and Mitsuya et al., Science, 249: 1533-1544 (1990). Nucleoside derivatives, such as AZT, which inhibit the viral reverse transcriptase, were among the first clinically active agents available commercially for anti-HIV therapy. Although very useful in some patients, the utility of AZT and related compounds is limited by toxicity and insufficient therapeutic indices for fully adequate therapy. Also, given the subsequent revelations about the true dynamics of HIV infection (Coffin, Science, 267: 483-489 (1995); and Cohen, Science, 267: 179 (1995)), it has become increasingly apparent that agents acting as early as possible in the viral replicative cycle are needed to inhibit infection of newly produced, uninfected immune cells generated in the body in response to the virus-induced killing of infected cells. Also, it is essential to neutralize or inhibit new infectious virus produced by infected cells.
Effective means for preventing HIV infection also are needed as a global priority. Heterosexual transmission accounts for the majority of new cases of HIV infection each year. Current reports from the World Health Organization estimate that a total of more than 40 million people are now infected with HIV. HIV prevention research has to date focused predominantly on vaccine development. However, no effective preventative or therapeutic vaccine has been identified thus far. New approaches to vaccine development, as well as entirely different strategies and agents for preventing person-to-person transmission of HIV infection, are needed. One approach showing great promise is the development and use of topical microbicides. In this approach, a suitable antiviral agent is applied directly at the potential site of virus exposure, e.g., the genital mucosa in the case of HIV. A suitable antiviral agent is one which inactivates or inhibits infectivity of a virus upon contact of the antiviral agent with the virus. Suitable animal models are available for demonstrating in vivo efficacy of such approaches for preventing transmission of immunodeficiency viruses, such as HIV. For instance, the HIV-inactivating protein, cyanovirin-N, has been shown to inhibit the sexual transmission of a chimeric simian/human immunodeficiency virus (SHIV) infection in a primate model employing macaques exposed to the virus vaginally or rectally (C-C Tsai et al., AIDS Res. Hum. Retroviruses, 19, 535-541 (2003) and C-C Tsai et al., AIDS Res. Hum. Retroviruses, 20, 11-18 (2004)).
Infection of people by influenza viruses is also a major cause of pandemic illness, morbidity and mortality worldwide. The adverse economic consequences, as well as human suffering, are enormous. Available treatments for established infection by this virus are either minimally effective or ineffective; these treatments employ amantatadine, rimantadine and neuraminidase inhibitors. Of these drugs, only the neuraminidase inhibitors are substantially active against multiple strains of influenza virus that commonly infect humans, yet these drugs still have limited utility or efficacy against pandemic disease.
Currently, the only effective preventative treatment against influenza viral infection is vaccination. However, this, like the drug treatments, is severely limited by the propensity of influenza viruses to mutate rapidly by genetic exchange, resulting in the emergence of highly resistant viral strains that rapidly infect and spread throughout susceptible populations. In fact, a vaccination strategy is only effective from year-to-year if the potential pandemic strains can be identified or predicted, and corresponding vaccines prepared and administered early enough that the year's potential pandemic can be aborted or attenuated. Thus, new preventative and therapeutic interventions and agents are urgently needed to combat influenza viruses.
New agents with broad anti-influenza virus activity against diverse strains, clinical isolates and subtypes of influenza virus would be highly useful, since such agents would most likely remain active against the mutating virus. The two major types of influenza virus that infect humans are influenza A and B, both of which cause severe acute illness that may include both respiratory and gastrointestinal distress, as well as other serious pathological sequellae. An agent that has anti-influenza virus activity against diverse strains and isolates of both influenza A and B, including recent clinical isolates thereof, would be particularly advantageous for use in prevention or treatment of hosts susceptible to influenza virus infection.
The predominant mode of transmission of influenza viral infection is respiratory, i.e., transmission via inhalation of virus-laden aerosolized particles generated through coughing, sneezing, breathing, etc., of an influenza-infected individual. Transmission of infectious influenza virions may also occur through contact (e.g., through inadvertent hand-to-mouth contact, kissing, touching, etc.) with saliva or other bodily secretions of an infected individual. Thus, the primary first points of contact of infectious influenza virions within a susceptible individual are the mucosal surfaces within the oropharyngeal mucosa, and the mucosal surfaces within the upper and lower respiratory tracts. Not only do these sites comprise first points of virus contact for initial infection of an individual, they are also the primary sites for production and exit (e.g., by coughing, sneezing, salivary transmission, etc.) of bodily fluids containing infectious influenza viral particles. Therefore, availability of a highly potent anti-influenza virus agent, having broad-spectrum activity against diverse strains and isolates of influenza viruses A and B, which could be applied or delivered topically to the aforementioned mucosal sites of contact and infection and transmission of infectious influenza viruses, would be highly advantageous for therapeutic and preventative inhibition of influenza viral infection, either in susceptible uninfected or infected hosts.
Highly pathogenic avian H5N1 influenza A viruses have been of widespread concern in recent years. The H5N1 virus can be highly lethal to birds and humans raising concerns of a possible pandemic (Hatta and Kawaoka, Uirusu. 55(1):55-61 (2005)). The well-established pathogenicity of these avian influenza viruses makes evident the need in the art for the development of effective anti-H5N1 drugs and vaccines.
Infection with hepatitis C virus (HCV) also represents an important public health problem. HCV is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (Verslype et al., Acta Gastroenterol Belg. 68(3):314-318 (2005)). Patients with HCV are mainly treated today with interferon, alone or in combination with ribavirin. However, such treatments eliminate the virus from only about one half of the patients (Watashi and Shimotohno, Uirusu. 55(1):105-110 (2005)). Therefore, a more effective approach to the treatment of HCV infection is needed.
In the latter part of 2002, a new disease, severe acute respiratory syndrome (SARS), emerged in China, and an animal coronavirus that had crossed the species barrier through close contact of humans with infected animals was later identified as the etiological agent. The coronavirus rapidly adapted to the new host and not only became readily transmissible between humans but also more pathogenic. Air travel spread the virus rapidly around the world and ultimately the virus infected 8096 people and caused 774 deaths in 26 countries on 5 continents. Aggressive quarantine measures successfully terminated SARS (Stadler and Rappuoli, Curr Mol Med. 5(7):677-697 (2005)). However, a resurgence of SARS is still a threat, because the causative agent remaining in animal reservoirs is not fully understood, and sporadic cases continue to be reported (Lu et al., Acta Pharmacol Sin. 26(12):1479-1484 (2005)). Therefore, there is a need in the art to develop antiviral drugs and vaccines specific for the SARS virus.
The Zaire ebola virus has caused large outbreaks of severe and usually fatal hemorrhagic disease in humans for which there is no effective treatment or cure (Towner et al., Virology 332(1):20-27 (2005)). Thus, there is a need in the art for effective methods of treating or preventing ebola viral infections in humans.
In this regard, new classes of anti-viral agents, to be used alone or in combination existing anti-viral agents, are needed for effective anti-viral therapy. New agents are also important for the prophylactic inhibition of viral infection. In both areas of need, the ideal new agent(s) would act as early as possible in the viral life cycle; be as virus-specific as possible (i.e., attack a molecular target specific to the virus but not the host); render the intact virus noninfectious; prevent the death or dysfunction of virus-infected cells; prevent further production of virus from infected cells; prevent spread of virus infection to uninfected cells; be highly potent and active against the broadest possible range of strains and isolates of a given virus; be resistant to degradation under physiological and rigorous environmental conditions; and be readily and inexpensively produced.
In view of the foregoing, there is a need in the art for new methods and compositions for inhibiting viral infection. The invention provides such methods. These and other advantages of the invention, as well as additional inventive features, will become apparent from the description provided herein.